Clinical family screening as a diagnostic tool for unknown-cause sudden cardiac death

31 Dec 2013

Sudden cardiac death (SCD) is generally defined as natural, unexpected death within 1 hour of the onset of symptoms.1 Nonspecific prodromal symptoms, for example, chest pain, palpitations, or dyspnea, can be present during the days or weeks before a cardiac arrest.2SCD remaining unexplained after thorough postmortem investigation is termed unknown-cause SCD. In at least 4% of sudden death cases, a full coroner’s post-mortem, a toxicological screening and an expert cardiac autopsy fail to reveal any underlying cause of death.3,4 Tan et al. data were published from the comprehensive evaluation of 43 families with a high frequency of unexplained SCD. Seventeen (40%) were identified with inherited cardiac disease including catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, Brugada syndrome, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), stressing the importance of defining the cause of death for appropriate prophylaxis of family members.4At the present case, we describe the case of a young woman who died suddenly. Postmortem examination was unremarkable, however, further investigation and familial clinical evaluation finally identified the cause of death.

Case report:

A 23-year-old female professional dancer died suddenly following physical activity. Routine postmortem examination failed to establish the cause of death. No cardiac structural abnormalities were revealed. She had a history of presyncopal episodes during the last two months preceding her SCD. Following the proband’s death, her family was referred to our department for clinical evaluation. During the course of clinical investigation and search for retrospective clinical data, an ECG of the young woman taken six months prior to her death was brought to light: it showed inverted T-waves in leads V1 and V2 as well as in leads II, III and aVF (Figure 1A).

Figure 1A.

Following informed consent, family members (Figure 1B) were evaluated with a standard protocol. All individuals underwent detailed non-invasive evaluation including clinical examination, 12-lead resting electrocardiogram (ECG), two-dimensional (2-D) and Doppler echocardiography, signal-averaged electrocardiography (SAECG), 24-hour Holter monitoring and exercise testing. In some cases, family members were additionally evaluated with magnetic resonance imaging and contrast echocardiography.

Figure 1B

Family clinical findings

The proband’s uncle was the first family member to undergo clinical investigation. He had been diagnosed with ARVC/D almost 5 years before his niece’s SCD. Resting 12-lead ECG exhibited negative T-waves in leads V1 to V3 (Figure 2A), his SAECG was positive for late potentials and 24-hour Holter monitoring recorded >1000 ventricular ectopic beats (VEBs) and episodes of non-sustained ventricular tachycardia (VT).

The patient fulfilled 1 major plus 3 minor criteria for ARVC/D diagnosis.5 During electrophysiological study, sustained VT of left bundle branch block morphology (LBBB) with both superior and inferior axis was induced. He received an implantable cardioverter-defibrillator and was discharged with a diagnosis of typical ARVC. Unfortunately, the rest of the family was not informed about the hereditary nature of the disease and family screening of first-degree relatives was not performed.The proband’s father had also been previously undergone evaluation for palpitations which failed to appreciate abnormalities consistent with ARVC/D. At that time, only hypertension was diagnosed and the patient was put on medication. When he was reevaluated after his daughter’s SCD, he had inverted T-waves in all precordial leads (Figure 3A), he was positive for late potentials, and >1000/day VEBs on Holter monitoring were recorded. 12-lead ECG displayed VEBs with LBBB morphology and inferior or superior axis.

Cardiac evaluation of proband’s sister, cousins and paternal aunt with clinical examination, 12-lead and 24-hour ambulatory ECG, SAECG, and 2-D echocardiography was negative.With both her father and uncle affected by ARVC/D, we were highly suspicious about a subclinical form of this disease that might have been the cause of young woman’s SCD. However, diagnosis was borderline: it was fulfilled only 1 major (family history of ARVC) and 1 minor (inverted T waves in leads V1-V2) criteria. 5 It was clear that we needed more data in order to “bind” an ARVC/D diagnosis to this unexplained SCD.